The primary objective of insulin therapy in the treatment of metabolic disorders is to produce sustained near-normal glycemia by replacing or supplementing endogenous insulin secretion in as physiological a manner as possible, post-prandially as well as between meals and overnight. Separating basal and meal-related (bolus) insulin requirements represents a systematic approach to subcutaneous insulin therapy.
The most relevant pharmacological characteristics of any given insulin—onset of action, peak effect profile, duration of action, etc.—are largely determined by its absorption kinetics from the subcutaneous injection site into the systemic circulation.
Non-covalent zinc mediated oligomerisation is a well-described property of insulin products. Under physiological pH, human insulin is soluble but has a tendency to self-associate into well-defined hexamers (i.e. a unit of six insulin molecules), by coordination of two zinc ions (Zn++) to high affinity (B10His) binding sites. It is also well-known that phenolic ligands, especially phenol, bind specifically to the insulin hexamer and promote R-state hexamer formation. Upon injection, phenolic ligands diffuses quickly from the injection site. In the absence of phenol at the injection site, the conformation and size of the insulin oligomer may change, as well as the viscosity of the insulin-containing solution, contributing to a prolonged action profile.
Jonassen et al, Pharm. Res. 2012 29 2104-2114 describe the protraction mechanism of insulin degludec, an insulin derivative with acylated fatty di-acid chain for once-daily administration, and describe the correlation between high zinc concentration and the protraction. WO 2009/115469 describes various long-acting insulin derivatives with acylated fatty di-acid chains. WO 2013/153000 describes the formulation of those long-acting insulin derivatives for subcutaneous administration, which contains high level of zinc (no less than 3.5 Zn++/six moles of insulin derivatives). It was designed in order to obtain the prolonged duration of action commensurate with a once-weekly administration profile. High content of Zn++ in the formulations described in WO 2009/115469 lead to a prolonged PK profile.
WO 2009/063072 discloses pharmaceutical compositions for parenteral administration comprising a basal insulin derivative (e.g. degludec) and a GLP-1 derivative (e.g, liraglutid). Because liraglutide monomer binds with zinc to form di-heptmer, zinc level higher than the degludec mono formulation is necessary in the combo formulation, to achieve comparable PK profile of degludec, and achieve acceptable physical stability.